1) In a series of experiments, we have shown that 2 new approaches, a ferrous iron chelator and intracarotid infusion of nitric oxide (NO) donor, reverse and prevent vasospasm after subarachnoid hemorrhage in primates. We are planning a pilot clinical study of intracarotid infusion of the NO donor in humans forreversal/prevention of vasospasm. Furthermore, on the basis of recent encouraging results of intravenous effect of NO donor on the vessels in brain tumors, we will study the effects of iv infusion of NO donor in vasospasm. To further our understanding of vasospasm, as well as to develop new strategies for its treatment, we are studying the influence of different compounds on NO synthase and NO production in a series of in vitro experiments in astrocytes, smooth muscle cells, endothelial cells, and glioma cells, using immunohistochemistry and an in vitro NO probe. 2) We have shown that an intracarotid (IC) infusion of ProliNO (a Nitric Oxide donor) a) quenches oxygen free radical production and b) reduces the volume of brain infarction in a rat model of global transient cerebral ischemia. We will continue experiments with the use of ProliNO in two different models of transient ischemia: a rat middle cerebral artery transient occlusion model and a rabbit embolism model. The hypothesis for those experiments is that the limited efficacy of r-tPA used in humans for treatment of ischemic stroke is due to damage generated upon brain reperfusion, and it is primarily mediated by oxygen free radical generation. In acute experiments with the rat model, we observed a significant decrease of stroke volume by intracarotid infusion of ProliNO. This effect was comparable to the use of a new oxygen free radical scavenger (Tempol). In the rabbit model, we measured an abrupt increase in the free radical generation immediately after embolism. Consequently, we are continuing experiments in this model to assess the influence of ProliNO and free radical scavenger (Tempol) on stroke volume and production of oxygen free radicals and NO by the brain during and after ischemia. 3) Temporary vascular occlusion is an important part of neurosurgery, but the capacity to monitor the effects of occlusion in real time has been limited. In circumstances that require temporary vascular occlusion during surgery (aneurysms, AVMs, tumors, etc.), the ability to visualize flow in the vessels and their distribution bed would be beneficial. During the use of a sensitive (0.02 dagC), high-resolution (up to 50mm), and rapid (up to 2msec/frame) infrared camera for localizing cortical function during surgery, we observed imaging of the cerebral arteries and veins with striking resolution. This approach for detecting sudden changes in blood flow in cerebral vessels and brain is being examined.